Public Release: 12-Aug-2008
Also in the August 12 JNCI

Infection with hepatitis B virus (HBV) causes liver cancer in some individuals, but not all strains of the virus are associated with the same degree of risk. If confirmed, the newly reported data could help target chemoprevention strategies in the future.

Researchers have previously identified eight genotypes of HBV and a variety of mutations in two regions of the viral genome, referred to as the precore and the basal core promoter. It was not known the extent to which different HBV genotypes or mutations are associated with the risk for liver cancer, which is also called hepatocellular carcinoma.

To find out, Chien-Jen Chen, Sc.D., of the Academia Sinica in Taipei, Taiwan, and colleagues characterized the viral DNA from 2,762 Taiwanese individuals who were infected with the virus but had not been diagnosed with liver cancer at the time of blood collection, which occurred during 1991 and 1992.

After a total follow-up of 33,847 person-years, 153 of these subjects have been diagnosed with liver cancer. HBV genotype C and a particular mutation in the basal core promoter (A1762T/G1764A) were associated with increased risk of liver cancer, while a mutation in the precore region (G1896A) was associated with a decrease in risk.

These data may help identify individuals "who are at an increased risk for liver disease progression and would therefore potentially benefit from early interventions, such as reg¬ular screening to detect disease progression, and treatment," the authors write.

In an accompanying editorial, Josep Llovet, M.D., of Mount Sinai School of Medicine in New York and Anna Lok, M.D., of the University of Michigan Medical Center in Ann Arbor review the previously known risk factors for liver cancer, prevention strategies to reduce the risk of HBV infection, and treatments for individuals who have already developed liver cancer.

"One of the main challenges is to determine whether secondary prevention can be accomplished with new antiviral therapies for HBV infection," the editorialists write. When secondary prevention strategies are tested in large randomized trials, patients should be stratified by known risk factors, including viral genotype and mutations.

Few Pharmacologic Treatments of Cancer-Related Fatigue Available to Patients

There is limited evidence to support the use of methylphenidate and erythropoietin for the treatment of cancer-related fatigue in some patients, according to a systematic review of randomized controlled trials.

Cancer-related fatigue is a common problem for patients undergoing treatment and for cancer survivors. However, the underlying causes of the problem are largely unknown, and therefore, identifying targeted therapies that mitigate the problems has been challenging.

Ollie Minton, M.D., of St. George's University of London and colleagues performed a systematic review and meta-analysis of randomized controlled trials designed to evaluate the impact of a pharmacologic agents on cancer-related fatigue. The researchers identified 27 studies in the literature, which included 6,746 patients.

The psychostimulant methylphenidate appeared to reduce cancer-related fatigue by about 30 percent relative to placebo. Erythropoietin also appeared to reduce cancer-related fatigue by about 30 percent, compared with placebo, in anemic cancer patients who were undergoing chemotherapy. Darbopoetin appeared to reduce cancer-related fatigue only 13 percent in anemic patients relative to placebo. Other agents studied, including the antidepressant paroxetine, were no better than placebo.

"The overall effect sizes that we are reporting for all classes of drugs are small," the authors write. "The potential implications for current practice and future research should be tempered as a result of this finding."

The use of doxorubicin followed by zoledronic acid reduced tumor size substantially in a mouse model of breast cancer that does not have bone metastases.

Zoledronic acid is a bisphosphonate currently used for the treatment of cancer-related bone disease in a variety of malignancies, including breast cancer. Breast cancer patients are also frequently treated with the anthracycline doxorubicin. Previous preclinical studies have suggested that the combination of doxorubicin and zoledronic acid may reduce tumor growth in models in which bone disease is prominent.

To determine what impact the combination might have on breast cancer tumors in the absence of bone disease, Ingunn Holen, Ph.D., of the University of Sheffield, UK, and colleagues injected animals with breast cancer cells that do not readily metastasize to bone. They subsequently treated animals with each agent alone, the two agents given simultaneously, zoledronic acid followed 24 hours later by doxorubicin, or doxorubicin followed 24 hours later by zoledronic acid.

There was no difference in tumor size following treatment with either single agent or with zoledronic acid followed by doxorubicin, as compared with animals treated with saline. Tumor size was approximately halved in animals treated with the two drugs dosed simultaneously compared with animals treated with doxorubicin alone. However, the largest reduction in tumor growth occurred in animals treated with doxorubicin followed by zoledronic acid, which resulted in nearly complete destruction of the tumors. Sequential therapy with doxorubicin and zoledronic acid was shown to increase the fraction of tumor cells undergoing cell death and reduce the number of dividing cells.

"To our knowledge, this is the first report to show that doxorubicin and zoledronic acid inhibit subcutaneous breast tumor growth in vivo in a treatment sequence-specific fashion and in the absence of tumor-induced bone disease," the authors write. "Our data suggest that there may be benefits of combining zoledronic acid with cytotoxic agents for the treatment of patients with early-stage breast cancer."

The incidence of adenocarcinoma of the esophagus in the United States increased among both white men and women between 1975 and 2004.

The overall incidence of esophageal cancer has been climbing in white men, holding steady in white women, and decreasing in black men and women. Previous reports suggested that the increase in white men was due to an increase in one type of esophageal cancer called adenocarcinoma.

To get a more detailed picture of the population trends, Linda Morris Brown, Dr.P.H., of the National Cancer Institute and RTI International in Rockville, Md., and colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database. They identified 22,759 cases of esophageal cancer in white patients diagnosed between 1975 and 2004 and 9,526 of those were adenocarcinoma of the esophagus.

When they grouped the cases into five-year time periods, they found that the total age-adjusted rate for esophageal cancer in white men rose from 5.76 per 100,000 person-years in 1975-1979 to 8.34 per 100,000 person-years in 2000-2004. The increase in esophageal cancer was driven by a 463 percent increase in the rate of adenocarcinoma from 1.01 in the earliest five year period to 5.69 per 100,000 person-years in the last five year period. The overall rate of esophageal cancer remained constant across the study period in white women, at around 2.0 per 100,000 person-years. However, there was a 335 percent increase in the rate of adenocarcinoma during the study period from 0.17 to 0.74 per 100,000 person-years, while the rate of squamous cell carcinoma declined.

"Our data indicate that the increase in adenocarcinoma is real and a growing health problem for both white men and women," the authors write. Recent data indicate that increases in obesity, particularly abdominal obesity, and gastroesophageal reflux disease may account for part of the upward trend in the incidence of ade¬nocarcinoma.

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